Nucleophosmin (NPM1) is a multifunctional protein involved in the regulation of centrosome duplication, ribosome biogenesis, genomic stability, histone chaperone function, and transcription. Overexpression of NPM1 is associated with cancers of diverse histological origins. Here, we have found that p300-mediated acetylation of NPM1 modulates its subcellular localization and augments its oncogenic potential. Acetylated NPM1 is predominantly localized in the nucleoplasm, where it associates with transcriptionally active RNA polymerase II. Deacetylation of NPM1 is brought about by human SIRT1 and reduces its transcriptional activation potential. Remarkably, increased levels of acetylated NPM1 were found in grade II and III oral squamous cell carcinoma (OSCC) patient samples. Small interfering RNA (siRNA)-mediated knockdown of NPM1 in an OSCC cell line, followed by microarray analysis and chromatin immunoprecipitation experiments, revealed that some of the genes involved in oral cancer malignancy are regulated by NPM1 and have acetylated NPM1 localized at their promoters. Either suppression of p300 by siRNA or mutation of acetylatable lysine residues of NPM1 resulted in reduced occupancy of acetylated NPM1 on the target gene promoter concomitant with its decreased transcript levels. These observations suggest that acetylated NPM1 transcriptionally regulates genes involved in cell survival and proliferation during carcinogenesis.

Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self-renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage-derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms.

Despite extensive progress in developing anticancer therapies, therapy resistance remains a major challenge that promotes disease relapse. The changes that lead to therapy resistance can be intrinsically present or may be initiated during treatment. Genetic and epigenetic heterogeneity in tumors make it more challenging to deal with therapy resistance. Recent advances in genome-wide analyses have revealed that the deregulation of distal gene regulatory elements, such as enhancers, appears in several pathophysiological conditions, including cancer. Beyond the conventional function of enhancers in recruiting transcription factors to gene promoters, enhancer elements are also transcribed into noncoding RNAs known as enhancer RNAs (eRNA). Accumulating evidence suggests that uncontrolled enhancer activity with aberrant eRNA expression promotes oncogenesis. Interestingly, tissue-specific, transcribed eRNAs from active enhancers can serve as potential therapeutic targets or biomarkers in several cancer types. This review provides a comprehensive overview of the mechanisms of enhancer transcription and eRNAs as well as their potential roles in cancer and drug resistance.